Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.
J Nucl Med. 2010 Jan;51(1):92-7. doi: 10.2967/jnumed.109.064659. Epub 2009 Dec 15.
Receptor for advanced glycation end products (RAGE) binds advanced glycation end products and other inflammatory ligands and is expressed in atherosclerotic plaques in diabetic and nondiabetic subjects. The higher expression in diabetes mellitus corresponds to the accelerated course of the atherosclerosis. This study was designed to test the hypothesis that the level of RAGE expression in atherosclerosis can be detected by quantitative in vivo SPECT and that counts in the target will correlate with the strength of the biologic signal.
A monoclonal murine antibody was developed against the V-domain of RAGE, fragmented into F(ab')(2) and labeled with (99m)Tc, and injected at a dose of 15.14 +/- 1.23 MBq into 24-wk-old male apolipoprotein E null (ApoE(-/-)) mice (n = 22), including mice with streptozotocin-induced diabetes mellitus (n = 8), nondiabetic mice (n = 8), and control ApoE(-/-)/RAGE(-/-) double-knock-out mice (n = 6). Four hours later (allowing for blood-pool clearance), the mice were imaged and sacrificed, and the proximal aorta was removed and counted to calculate the percentage injected dose of RAGE per gram of tissue, followed by histologic and immunohistochemical characterization.
Radiotracer uptake in the aortic lesions was clearly visualized noninvasively by SPECT. RAGE uptake as percentage injected dose in diabetic ApoE(-/-) mice (1.39 +/- 0.16 x 10(-2)) was significantly higher than that in nondiabetic ApoE(-/-) mice (0.48 +/- 0.27 x 10(-2)) (P < 0.0001). The radiotracer uptake was highly correlated with RAGE expression by quantitative immunohistomorphometry (r = 0.82, P = 0.002) and with percentage of macrophages (r = 0.86, P < 0.0001).
In this study, (99m)Tc-labeled anti-RAGE F(ab')(2) SPECT successfully identified early accelerated disease in diabetes mellitus for age-matched ApoE(-/-) mice and quantified RAGE expression over a range of lesion severities.
检测受体（RAGE）在动脉粥样硬化中的表达水平，探讨其与动脉粥样硬化病变程度的关系。
用抗 RAGE 的单克隆抗体 F（ab'）2 片段标记 99mTc，对 24 周龄雄性载脂蛋白 E 基因敲除（ApoE-/-）小鼠（包括链脲佐菌素诱导的糖尿病组 8 只、非糖尿病组 8 只及 ApoE-/-/RAGE-/- 双基因敲除对照组 6 只）进行静脉注射，剂量为 15.14±1.23MBq。4 小时后进行 SPECT 扫描，处死小鼠，取主动脉进行放射性计数，计算单位重量组织的放射性摄取率，并行病理和免疫组化分析。
SPECT 能清晰显示主动脉病变部位的放射性摄取。糖尿病组的 RAGE 摄取率（1.39±0.16×10-2）明显高于非糖尿病组（0.48±0.27×10-2）（P<0.0001）。放射性摄取率与定量免疫组化分析的 RAGE 表达（r=0.82，P=0.002）和巨噬细胞百分数（r=0.86，P<0.0001）均呈显著正相关。
本研究应用 99mTc 标记的抗 RAGE F（ab'）2 SPECT 成功地对糖尿病 ApoE-/- 小鼠进行了早期动脉粥样硬化病变的检测，并对不同严重程度的动脉粥样硬化病变进行了 RAGE 表达的定量分析。
